Novel biologically active substituted-s-triazines

ABSTRACT

Novel biologically active substituted-s-triazines having antiinflammatory action of the formula   AS WELL AS THEIR PHARMOLOGICALLY ACCEPTABLE ACID ADDITION SALTS WITH ORGANIC AND INORGANIC ACIDS WHEREIN X is an N-cycloalkyldiimine radical, preferably, a piperazine or homopiperazine radical or their N&#39;&#39;-alkyl, N&#39;&#39; -alkylol or N&#39;&#39;-acyl substitution products in which the alkyl or alkylol groups contain one to six carbon atoms and the acyl radicals are   WHEREIN EACH Y and Y&#39;&#39; is hydrogen, halogen, -NO2, -alkyl, -Oalkyl, -OH or COOH, wherein the alkyl has up to six carbon atoms and R2 is   PIPERAZINO, HOMOPIPERAZINO, PIPERIDINO OR PYRROLIDINO, WHEREIN EACH OF R, R3 and R4 is hydrogen or an alkyl group of one to six carbon atoms or an aryl group, R5 is lower alkyl, cycloalkyl, alkyl aryl, each of R6 and R7 is hydrogen, alkyl of one to six carbon atoms, morpholino alkyl, piperazino alkyl, homopiperazino alkyl, hydroxy alkyl, alkylene diamine whose second nitrogen atom may be substituted by alkyl or phenyl, the alkyl and alkylene included in R1-R7 having from one to six carbon atoms and the aryl preferably being phenyl.

United States Patent Werner Heimberger Hanan am Main, Germany [21 1Appl. No. 685,258

[72] Inventor [22] Filed Nov. 24,1967

[45] Patented Dec. 7, 1971 [73] Assignee Deutsche Gold-undSllber-Scheidean-Stalt vormals Roessler Franklurt am Main, Germany [32]Priority Nov. 24, 1966 [3 3 Germany The portion of the term of thepatent subsequent to May 25, 1988, has been disclalmed.

[54] NOVEL BIOLOGICALLY ACITIVE SUBSTITUTED- S-TRIAZINES 5 Claims, NoDrawings [52] U.S. Cl ..260/247.5R, 260/2472 B, 260/249.6, 260/240 0,424/248, 424/249 [5| Int. Cl C07d 55/22 [50] Field of Search 260/240 G,

[56] References Cited UNITED STATES PATENTS 3,178,423 4/l965 Staehelinet al. 260/240 3,3 10,557 3/1967 Kleemann 260/2496 Primary Examiner-JohnM. Ford Attorney-Stephens, Huettig & OConnell ABSTRACT: Novelbiologically active substituted-s-triazines having anti-inflamnflqaction g flhefgrrnula as well as their pharmologically acceptable acidaddition salts with organic and inorganic acids wherein X is anN-cycloalkyldi-imine radical, preferably, a piperazine or homopiperazineradical or their N'-alkyl, N'-alkylol or N'-acyl substitution productsin which the alkyl or alkylol groups contain one to six arhon tgms andthe acyl radicals are wherein the Alk is alkylene and the alkyl andalkylene have up to six carbon atoms, R is one of the radicals whereineach Y and Y is hydrogen, halogen, NO alkyl, Oalkyl, OH or COOl-l,wherein the alkyl has up to six satlzena qm nd R2 is morpholino,piperazino, homopiperazino, piperidino or pyrrolidino, wherein each ofR, R and R is hydrogen or an alkyl I group of one to six carbon atoms oran aryl group, R is lower NOVEL BIOLOGICALLY ACTIVE SUBSTITUTED-S-TRIAZINES BACKGROUND OF THE INVENTION The invention concerns Novelsubstituted -s-triazine compounds having antiinflammatory activity.

It is known that compounds of the formula and their salts, wherein R andR are lower hydrocarbon radicals of aliphatic character, the aliphaticchain of which may be interrupted by heteroatoms, such as oxygen,nitrogen or sulfur, or disubstituted amino groups and R is hydroazinosubstituted with at least one substituted or unsubstituted hydrocarbonradical of aliphatic character, the aliphatic chain of which may beinterrupted, are marked by their special blocking action (GermanPublished application 1,163,840).

DESCRIPTION OF THE INVENTION Including Preferred Embodiments The presentinvention concerns novel compounds of the formula I described above, aswell as their pharmacologically acceptable acid addition salts.

These compounds can be prepared by:

a. first reacting a tris-halogen-s-triazine, preferablytrischloro-s-triazine with a compound of the formula in a known mannerto produce a compound of the formula Z l C N N t HalC Hal N III whereinHal is halogen and Z is a radical of one of the compounds of theformulas lla, [lb and [I and reacting such compound of formula III witha compound of the formula HX (IV) or HR (V) (piperazine andhomopiperazine being excluded if only monopiperazino ormonohomopiperazino compounds are to be prepared) to produce a compoundof the formula and then if desired reacting such compound with apiperazine or homopiperazine,

b. reacting the tris-halogems-triazine first with a compound of formulaIV or V and then with a compound of formula, lla, llb or [[0,preferably, without isolation and then if necessary thereafter with thepiperazine or homopiperazine,

c. reacting a compound of the formula VI or V" with the piperazine orhomopiperazine (when only monopiperazino or homopiperazino are to beprepared, reacting a compound of the formula VI wherein piperazine andhomopiperazine, are excluded from the definition of R with thepiperazine or homopiperazine),

d. reacting a compound of the formula in which A is SH, SAlk, -OAlk oraccording to one of the methods a., b. or 0, whereby piperazine orhomopiperazine may also be introduced in a second position and ifdesired acylating the compound containing a cycloalkyldi-imine radicalwith an acid chloride or acid ester and/or if desired converting thecompounds to their salts.

The preparation of the compounds which involves conventional methodscan, for instance, be carried out by dissolving the starting triazinecontaining one or more halogen atoms in an organic solvent, such as,acetone or methylene chloride and then adding at least an equimolecularquantity of the amine concerned. It is also possible, however, tooperate in aqueous suspensions.

The reaction preferably is carried out in the presence of an acidbinding agent. Depending upon the substituents concerned the reactioncan be carried out :at room temperature, or above or below roomtemperature.

All acids normally employed in the production of medicament salts can beused for the production of the salts of the compounds according to theinvention, such as, for example, lHCl HBr, H SOr maleic acid, fumaricacid molonic acid, acetic acid and the like.

The compounds according to the invention possess valuable pharmaceuticalproperties and are especially valuable because of their antiphlogisticand analgesic action upon oral, enteral and parenteral administration.

The compounds, for example, upon oral administration in doses of l to300 mg./kg. exhibit a strong antiphlogistic action on ovablum edema ofthe rat paw. The compounds upon oral administration to rats act tonic indoses over 200 mg./kg. and in some instances l0,000 mgJkg.

In addition, the compounds upon oral administration in doses of IO to500 mg./kg. have a strong analgesic action. (Haffner-test, Dtsch. Med.Wschr. 55, 731 (I929) The following examples will serve to illustratethe compounds according to the invention and their preparation.

The following examples will serve to illustrate the novel compoundsaccording to the invention.

EXAMPLE 1 553.5 g. of cyanuric chloride (3 MOL) were dissolved in 2liters of acetone and 26l.5 g. of morplholine (3 mol) added dropwiseover a period of 1 hour at 0 to 5 C. In order to complete the conversionof the morpholine a solution of g. of NaOl-I (3 mol) in 400 ml, of waterwere added under the same conditions. The triazine compound whichprecipitated was filtered off and dissolved in 400 ml. of methylenechloride to separate it from the water. Such solution was then driedwith anhydrous Na,SO After the methylene chloride was distilled off, 237g. of 2-morpholino-4,6-bichloro-s-tirazine of a melting point of 130 C.(decomposition) were obtained. The yield was 33.5 percent of theory, theproduct was 97 percent pure. A further quantity could be recovered fromthe mother liquor.

23.5 g. of the product (one-tenth mol) were dissolved in 300 ml. ofacetone and 9.31 g. of aniline (one-tenth mol) added dropwise thereto atroom temperature over a 30 minute period. The reaction of the anilinewas completed by addition of 4 g. of NaOH (l/; mol) in 50 ml. of 11,0under the same conditions. The triazine compound with precipitated wasfiltered off, washed with water and dried. 22.6 g. of 2-morpholino-4-anilino-6-ch1oro-s-triazine of a melting point of 165-170C. were obtained. The yield was 77.4 percent of theory.

Sixty-nine grams of the compound (0.237 mol) were introduced into aboiling solution of 130 g. of piperazine hexahydrate (3X0.237 mol) in 40ml. of ethanol and the mixture heated under reflux for 30 minutes. Thesolution was then concentrated under vacuum and the residue dissolved in300 ml. of methylene chloride, washed with water, dried with Na,SO andconcentrated. Crystallization was engendered in the residue by treatmentwith methylene chloride-hexane (3:7). 53.2 g. of2-anilino-4-morpho1ino-6-piperazino-striazine with a melting point of160-l63 C. were obtained. The yield was 65.6 percent of theory.

EXAMPLE 2 184.5 g. of cyanuric chloride (1 mol) were dissolved in 1,400ml. of acetone and 186.26 g. of aniline (2 mol) added dropwise theretowhile stirring at 0 to 5 C. over a period of 1 hour. The anilinehydrochloride which precipitated out was filtered off and the acetonesolution concentrated under vacuum. The residue was washed with icewater and filtered tion of a solution of 4 g. of NaOH in 50 ml. of waterunder the same conditions. The triazine compound which precipitated outwas filtered off, washed with water and dried. Twenty-four grams of2-anilino-4-morpholino-6-chloro-s-triazine (98 percent) with a meltingpoint of 192l95 C. were obtained. This compound was reacted withpiperazine hexahydrate to produce the2-ani1ino-4-morpholino-6-piperazino-s-trazine as described in example 1.

EXAMPLE 3 Seventy-nine grams of 2-(2-chloro)-anilino-4-morpholino-6-chloro-s-triazine (0.242 mol) with a melting point of 156159 C. werereacted with piperazine hexahydrate as described in example 1. 63.2 g.of 2-(2-chloro)-anilino-4- morpholino-6-piperazino-s-traizine of amelting point of 145- 149 C. were obtained. The yield was 69.5 percentof theory.

EXAMPLE 4 46.1 g. of cyanuric chloride (0.25 mol) were dissolved in 600ml. of acetone and 69 g. of 3-nitroaniline (0.5 mol) added portionwisethereto at room temperature while stirring. After stirring for a further3 hours the 3-nitroaniline hydrochloride which precipitated out wasfiltered ofi and then 43.6 g. morpholine (0.5 mol) were added to thesolution dropwise within a 30 minute period under the same conditions.The triazine compound precipitated out together with the morpholinehydrochloride. The triazine compound was recovered from the precipitateafter removal of the solvent by washing with water. 63.5 g. of 2-(3-nitro)-anilino-4- morpholino-6-chloro-s-triazine (98 percent) with amelting point of 244-249 C. were obtained. The yield was 75.4 percent oftheory.

63.5 g. of the product thus produced (0.188 mol) were added portionwisewhile stirring to a boiling solution of 1 10 g. of piperazinehexahydrate (3X0.188 mol) in 600 ml. of ethanol over a 60 minute periodand the mixture heated for a further 30 minutes. When the resultingsolution was stored overnight at room temperature the byproducts(dimers) separate out and these were filtered off. The solution wasconcentrated and the residue washed with water and dried.

66.1 g. of 2-(3-nitro)-anilino-4-morpholino-6-piperazino-striazinepercent) with a melting point of 190-173 C. were obtained. The yield was90.8 percent of theory.

EXAMPLE 5 46.1 g. of cyanuric chloride (0.25 mol) were dissolved in 500ml. of methylene chloride and 53.6 g. of o-toluidine (0.5 mol) addedthereto dropwise while stirring at 0 to -5 C. over a 30 minute period.The toluidine hydrochloride which precipitated out was filtered off and43.6 g. of morpholine (0.5 mol) added dropwise to the solution at roomtemperature during a 30 minute period. The morpholine hydrochloridewhich precipitated out was filtered off and the methylene chloridedistilled off from the solution. The residue was washed with water anddried. 73.5 g. of 2-(2-methyl)-anilino-4 -morpholino-6-chloro-s-triazinewith a melting point of 146-150 C. were obtained. The yield was 96.6percent of theory. This compound was reacted with piperazine hexahydrateas described in example 4 to product 2-(2-methyl)-anilino-4-morpholino--piperazino-s-triazine with a melting point of128-131C.

The procedure was repeated, however, using mand ptoluidine in place ofthe o-toluidine in the first step whereby 2-(3-methyl)-anilino-4-morpholino-6-chloro-s-triazine of a melting pointof 144-146 C. and 2-(4-methyl)-anilino-4- morpholino-6-chloro-s-triazineof a melting point of 205-207 C. were obtained. These compounds werereacted with piperazine hexahydrate again as described in example 4 toproduce the corresponding 2-(3-methyl)-anilino-4-morpholino-6-piperazino-s-triazine of a melting point of 109 to 114 C.and 2-(4-methyl)-ani1ino-4-morpholino-6- piperazino-s-triazine of amelting point of 1 80-190 C.

EXAMPLE 6 a. 46.1 g. of cyanuric chloride (0.25 mol) were dissolved in600 ml. of acetone and a solution of 39.4 g. of 4-chloro-2- anisidine(0.25 mol) in ml. of acetone added portionwise thereto while stirring at10 C. over a 30 minute period. The reaction was completed by addition ofa solution of 10 g. of

. NaOH (0.25 mol) in 60 ml. of water. Thereafter, 21.8 g. of

morpholine (0.25 mol) were added dropwise at room temperature and thereaction again completed by addition of a further 10 g. of NaOHdissolved in 60 ml. of water. The triazine compound which precipitatedout was filtered off, washed and dried. Eighty-one grams of2-(2-methoxy-4 chloro)-anilino-4-morpholino-6-ch1oro-s-triazine (95percent) with a melting point of l68l70 C. were obtained. The yield was91 percent of theory. This compound was reacted with piperazinehexahydrate as described in example 4 to produce2-(2-methoxy-4-morpholino-6piperzino's-triazine of a melting point of 1-182 C.

b. The procedure was repeated using 4-methoxy-aniline instead of the4-chloro-2-anisidine. The resulting 2-(4-methoxy)-anilino-4-morpholino-6-ch1oro-s-triazine had a melting point of146l50 C. and the 2-(4-methoxy)-anilino-4morpholino-6-piperazino-s-triazine had a melting point of205-208 c.

EXAMPLE 7 46.1 g. of cyanuric chloride (0.25 mol) were dissolved iil;600 ml. of acetone and a solution of 54.5 g. of p-aminophenol (0.5 mol)in 200 ml. of acetone added thereto portionwise at C. while stirringover a period of minutes. The hydrochloride of the p-aminophenol whichprecipitated out was filtered off and 43.6 g. of morpholine 0.5 mol)then added to the filtrate. The hydrochloride of the morpholineprecipitated out together with the triazine compound as described inexample 4. The processing was the same as in example 4. After washingand drying, 41.0 g. of 2-(4-hydroxy)-anilino-4-morpholino-6-chloro-s-triazine (98percent) with a meltingpoint of 194-197 C. were obtained. The yield was 59.1 percent of theory.This compound was reacted with piperazine hexahydrate as described inexample 4 to product2-(4-hydroxy)-anilin0-4-morpholino-6-piperazino-s-triazine of a meltingpoint of 208-212 C.

EXAMPLE 8 67.3 g. of 2-cyclohexylamino-4-morpholino-6-chloro-striazine(0.235 mol) were reacted with piperazine hexahydrate as described inexample 1. Fifty-three grams of 2-cyclohexylamino-4-morpholino-6-piperazino-s-triazine with a meltingpoint of 132-138 C. were obtained. The yield was 65.5 percent of theory.

EXAMPLE 9 The procedure of example 5 was repeated using anaphthylamineinstead of o-toluidine. The 2-(a)-naphthylamino'4-morpholino-6-chloro-s-tirazine produced had a meltingpoint of 204-208 C. and the 2-(a)-naphthylamino-4-morpholino-6-piperazino-s-triazine produced therefromwas a viscous oil.

EXAMPLE 10 a. 35.5 g. (0.1 mol) of 2-(3-methyl)-anilino-4-morpholino-6-piperazino s-triazine prepared as in example 6 were dissolved in 300ml. of methylene chloride at room temperature and 10.12 g. (0.1 mol) oftriethyl amine and 11.29 g. (0.1 mol) of chloroacetyl chloride addedthereto dropwise at the same time, whereupon the temperature of thesolution rose to 30 C. After the reaction mixture had been permitted tostand for 1 hour the solvent was distilled off and the residue washedseveral times with water. 41.5 g. of 2-(3-methyl)-anilino-4-morpholino-6-N'(chloroacetyl)piperazino-s-triazine were obtained. ltsmelting point was 143-45 C. and the yield 96.2 percent oftheory.

b. 43.15 g. of the product thus produced were added portionwise to asolution of 2.53 g. (0.11 mol) of Na and 10.34 g. of phenol (0.11 mol)in 400 ml. of ethanol. After 2 hours heating under reflux completesolution was effected. Upon cooling to room temperature NaClprecipitated out and this was filtered off. The ethanol was distilledoff and the residue washed with water. 34.7 g. of 2-(3-methyl)anilino-4-morpholino-6-4'N'-phenoxyacetyl-piperazino-s-triazine with a meltingpoint of 185-88 C. were obtained. The yield was 71 percent of theory.

EXAMPLE 1 1 37.5 g. of2-(2-chloro)-anilino-4-morpholino-6-piperazinos-triazine producedaccording to example 3 were dissolved in 500 ml. of methylene chlorideand then 1 1.13 g. (0.11 mol) added thereto. Subsequently, 11.93 g.(0.11 mol) of chloroformic acid ethyl ester were added dropwise whilestirring at room temperature, whereupon the temperature of the solutionrose to 35 C. After 1 hour's standing, the solution was washed twicewith water, then dried and the solvent distilled off. The residue waswashed with water and dried. 39.2 g. of2-(2-chloro)-anilino-4-morpholino-o-N-carboxyethyl-piperazino-s-triazineEXAMPLE 12 a. 46.1 g. (0.25 mol) of cyanuric chloride were suspended ina mixture of 600 ml. of acetone and 300 ml. of water and 26.8 g. ofm-toluidine added thereto over a 30 minute period while stirring andcooling to 0 to -5 C. Thereafter a solution of 10 g. of NaOH in 50 ml.of H 0 was added dropwise.

The reaction mixture is then heated to 25 C. (PH 7) and 21,25 g. (0.25mol) piperidine are added. After this a solution of 10 g. (0.25 mol)NaOH in 50 ml. H 0 is added dropwise in such a manner that the PH of 7did not change. After filtration 70 g. of2-(3-methyl)anilino-4-piperidlino6-chloro-s-triazine of a melting pointof 67-7 1 C. were obtained. The yield was 92.4 percent of theory.

Similarly, 70 g. of 2-( 4-methy|).anilino-4-piperidino-6-chloro-s-triazine with a melting point of 128l32 C. were obtained whenthe mto1uidine was replaced by p-toluidine b. 30.35 g. of each of thecompounds obtained above were respectively added portionwise to asolution of 58.2 g. of piperazine hexahydrate in ethanol boiling underreflux over a period of 3 hours, whereupon solution occurred. Thesolution was then allowed to stand overnight to separate out the dimericbyproducts. After filtration the ethanol was distilled off and theresidue washed with water until neutral and dried. The yield of thecompounds produced was 30.5 g. or 86.4 percent of theory.

The 2-(3-methyl)ani1ino-4-piperidino-o-piperazino-striazine had amelting point of -138 C. and the corresponding 2-(4-methyl)anilinocompound had a melting point of 1791 81 C. The maleates were prepared byintroducing the compounds into an equimolar solution of maleic acid inmethanol. The melting points of the salt produced respectively were 158C. with decomposition and C. with decomposition.

EXAMPLE 12 The procedure of example 1 1 (a) was repeated except thatm-anisidine was employed instead of the toluidines. Seventytwo grams of2-(3-rnethoxy)-anilino-4-piperidino-chloro-striazine of a melting pointof ll7120 C. (90.2 percent of theory) were obtained. When 31.95 g.thereof were reacted with piperazine hexahydrate as in example 1 1 (b),28.8 g. of 2- (3-methoxy)-anilino-4-piperidino-6-piperazino-s-triazinewith a melting point of 153-156 C. were obtained. The yield was 77.9percent of theory.

EXAMPLE 13 29.8 g. (0.1 mol) of 2-cyclohexylamino-4-morpholino-6-chloro-s-triazine were suspended in 250 ml. of ethanol and 2.0 g. (0.1mol) of N'methyl piperazine added thereto and the mixture heated underreflux for 1 hour, whereupon solution resulted. After the solvent wasdistilled off the residue was dissolved in methylene chloride and washedwith water.

After the methylene chloride was distilled off, 29 g. of 2-(cyclohexylamino-4morpho1ino-6-N'methyl-piperazino-striazine wereobtained. The yield was 80.3 percent of theory.

The compound was immediately converted to the maleic acid Alk beingalkylene, and the alkyl and alkylene included in M salt as in example 12(b). Thirty-five grams of the salt with a having up to six carbon atoms,R is selected from the group melting point of 203-207 C. were obtained.The yield was i tin of 73.4 percent of theory.

lclaim: Y 1. A triazine compound selected from the group consisting NHNH@, NH of compounds of the fonnula Y! R cc .c r... k MW H. r o No V Vwherein each of Y and Y are selected from the group consist- N ing ofhydrogen, chlorine, lower alkyl, lower alkoxy, --NO, RL-C gand -OH and Ris selected from the group consisting of morpholino and piperidino andtheir pharmacologically acceptable acid addition salts.

whereinXis 2. The compound according to claim 1, 2-(2-chloro)-anilino-4-morpholino-6-piperazino-s-triazine.

CRT-CH2 M 3. The compound according to claim 1, 2-(2-methyl)-anilino-4-morpholinc-6-piperazino-s-triazine. .7.-. We, W. 31195? 4. Thecompound according to claim 1, 2-(3-methyl)- wherein M is selected fromfrom the group consisting of amhno'4'morpholmo''plperazmo's'mazme'hydrogen,alkyl,alkylol, 5. The compound according to claim 1,2-(4-methyl)- C a1ky} and 0 phenylanilino-4-morpholino-o-piperazino-s-triazine.

(l-l) (H) g g t

2. The compound according to claim 1,2-(2-chloro)-anilino-4-morpholino-6-piperazino-s-triazine.
 3. Thecompound according to claim 1,2-(2-methyl)-anilino-4-morpholino-6-piperazino-s-triazine.
 4. Thecompound according to claim 1,2-(3-methyl)-anilino-4-morpholino-6-piperazino-s-triazine.
 5. Thecompound according to claim 1,2-(4-methyl)-anilino-4-morpholino-6-piperazino-s-triazine.